tbuckley/cabot-search huggingface dataset:
TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study
Authors: Yichuan Yuan, Wei He, Zhiwen Yang, Jiliang Qiu, Zhenkun Huang, Yunxing Shi, Zhu Lin, Yun Zheng, Minshan Chen, Wan Yee Lau, Binkui Li, Yunfei Yuan
Journal: International Journal of Surgery (2023)

The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT.
Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody
Authors: Marc S. Raab, Yael C. Cohen, Fredrik Schjesvold, Kimberly Aardalen, Adwait Oka, Andrew Spencer, Martin Wermke, Anita D. Souza, Jonathan L. Kaufman, Anna Maria Cafro, Enrique M. Ocio, Noriko Doki, Kristin Henson, Gina Trabucco, Ana Carrion, Florent C. Bender, Pierre-Eric Juif, Adonai Fessehatsion, Liqiong Fan, Jeffrey P. Stonehouse, John W. Blankenship, Brian Granda, Serena De Vita, Haihui Lu
Journal: Leukemia (2023)
Health4Life eHealth intervention to modify multiple lifestyle risk behaviours among adolescent students in Australia: a cluster-randomised controlled trial
Authors: Katrina E Champion, Nicola C Newton, Lauren A Gardner, Cath Chapman, Louise Thornton, Tim Slade, Matthew Sunderland, Leanne Hides, Nyanda McBride, Siobhan O'Dean, Frances Kay-Lambkin, Steve Allsop, David R Lubans, Belinda Parmenter, Katherine Mills, Bonnie Spring, Bridie Osman, Rhiannon Ellem, Scarlett Smout, Jesse Whife, Courtney Stewart, Karrah M McCann, Amra Catakovic, Emily Hunter, Maree Teesson
Journal: The Lancet Digital Health (2023)
RNA interference therapy in acute hepatic porphyrias
Authors: Makiko Yasuda, Siobán Keel, Manisha Balwani
Journal: Blood (2023)

Abstract The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to the accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications, including kidney disease and an increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetylgalactosamine–conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that the continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduced urinary ALA and porphobilinogen levels and acute attack rates and improved quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the US Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for the treatment of patients with AHP. Although givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in patients with AHP are lacking.
Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma
Authors: Gilbert Youssef, Rifaquat Rahman, Camden Bay, Wei Wang, Mary Jane Lim-Fat, Omar Arnaout, Wenya Linda Bi, Daniel N. Cagney, Yuh-Shin Chang, Timothy F. Cloughesy, Matthew DeSalvo, Benjamin M. Ellingson, Thomas F. Flood, Elizabeth R. Gerstner, L. Nicolas Gonzalez Castro, Jeffrey P. Guenette, Albert E. Kim, Eudocia Q. Lee, Jose R. McFaline-Figueroa, Christopher A. Potter, David A. Reardon, Raymond Y. Huang, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2023)

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.
Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process
Authors: Antero Salminen
Journal: Ageing Research Reviews (2023)

Circadian clocks control the internal sleep-wake rhythmicity of 24 h which is synchronized by the solar cycle. Circadian regulation of metabolism evolved about 2.5 billion years ago, i.e., the rhythmicity has been conserved from cyanobacteria and Archaea through to mammals although the mechanisms utilized have developed with evolution. While the aryl hydrocarbon receptor (AhR) is an evolutionarily conserved defence mechanism against environmental threats, it has gained many novel functions during evolution, such as the regulation of cell cycle, proteostasis, and many immune functions. There is robust evidence that AhR signaling impairs circadian rhythmicity, e.g., by interacting with the core BMAL1/CLOCK complex and disturbing the epigenetic regulation of clock genes. The maintenance of circadian rhythms is impaired with aging, disturbing metabolism and many important functions in aged organisms. Interestingly, it is known that AhR signaling promotes an age-related tissue degeneration, e.g., it is able to inhibit autophagy, enhance cellular senescence, and disrupt extracellular matrix. These alterations are rather similar to those induced by a long-term impairment of circadian rhythms. However, it is not known whether AhR signaling enhances the aging process by impairing circadian homeostasis. I will examine the experimental evidence indicating that AhR signaling is able to promote the age-related degeneration via a disruption of circadian rhythmicity.
Development and Validation of the Veterans Affairs Eosinophilic Esophagitis Cohort
Authors: Eric E. Low, Qingyuan Song, Rena Yadlapati, Evan S. Dellon, Seema Aceves, Lin Liu, Samir Gupta, Yash A. Choksi, Shailja C. Shah
Journal: Clinical Gastroenterology and Hepatology (2023)
Genome graphs detect human polymorphisms in active epigenomic state during influenza infection
Authors: Cristian Groza, Xun Chen, Alain Pacis, Marie-Michelle Simon, Albena Pramatarova, Katherine A. Aracena, Tomi Pastinen, Luis B. Barreiro, Guillaume Bourque
Journal: Cell Genomics (2023)

Genetic variants, including mobile element insertions (MEIs), are known to impact the epigenome. We hypothesized that genome graphs, which encapsulate genetic diversity, could reveal missing epigenomic signals. To test this, we sequenced the epigenome of monocyte-derived macrophages from 35 ancestrally diverse individuals before and after influenza infection, allowing us to investigate the role of MEIs in immunity. We characterized genetic variants and MEIs using linked reads and built a genome graph. Mapping epigenetic data revealed 2.3%–3% novel peaks for H3K4me1, H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq), and ATAC-seq. Additionally, the use of a genome graph modified some quantitative trait loci estimates and revealed 375 polymorphic MEIs in an active epigenomic state. Among these is an AluYh3 polymorphism whose chromatin state changed after infection and was associated with the expression of TRIM25, a gene that restricts influenza RNA synthesis. Our results demonstrate that graph genomes can reveal regulatory regions that would have been overlooked by other approaches.
Transposable elements are associated with the variable response to influenza infection
Authors: Xun Chen, Alain Pacis, Katherine A. Aracena, Saideep Gona, Tony Kwan, Cristian Groza, Yen Lung Lin, Renata Sindeaux, Vania Yotova, Albena Pramatarova, Marie-Michelle Simon, Tomi Pastinen, Luis B. Barreiro, Guillaume Bourque
Journal: Cell Genomics (2023)

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.
Happy 75th birthday World Health Organization
Authors: John Middleton, Selma Sogoric
Journal: BMJ (2023)

World Health Day this year marks the 75th birthday of the World Health Organization (WHO). 1 Founded alongside the United Nations, it was accompanied by a family of global organisations, including UNICEF, UNESCO, the World Bank, and the Food and Agriculture Organisation of the United Nations.Global policy governance was borne out of post war political optimism and a universal desire to address William Beveridge's five giant evils-want, idleness, ignorance, squalor, and disease.There was a vision to rebuild a fairer, cleaner, healthier, wiser, and productive global community.It was a time for the old colonial powers to retreat and for new independence to come to the Global South.
Re: Pain and Health-related Quality of Life with Olaparib Versus Physician’s Choice of Next-generation Hormonal Drug in Patients with Metastatic Castration-resistant Prostate Cancer with Homologous Recombination Repair Gene Alterations (PROfound): An Open-label, Randomised, Phase 3 Trial
Authors: Sola Adeleke, Aruni Ghose, Stergios Boussios
Journal: European Urology (2023)
Regulation of c-SMAC formation and AKT-mTOR signaling by the TSG101-IFT20 axis in CD4+ T cells
Authors: Jiung Jeong, In Kang, Yumin Kim, Keun Bon Ku, Jang Hyun Park, Hyun-Jin Kim, Chae Won Kim, Jeongwoo La, Hi Eun Jung, Hyeon Cheol Kim, Young Joon Choi, Jaeho Kim, Joon Kim, Heung Kyu Lee
Journal: Cellular and Molecular Immunology (2023)

Abstract CD4 + T cells play major roles in the adaptive immune system, which requires antigen recognition, costimulation, and cytokines for its elaborate orchestration. Recent studies have provided new insight into the importance of the supramolecular activation cluster (SMAC), which comprises concentric circles and is involved in the amplification of CD4 + T cell activation. However, the underlying mechanism of SMAC formation remains poorly understood. Here, we performed single-cell RNA sequencing of CD4 + T cells left unstimulated and stimulated with anti-CD3 and anti-CD28 antibodies to identify novel proteins involved in their regulation. We found that intraflagellar transport 20 (IFT20), previously known as cilia-forming protein, was upregulated in antibody-stimulated CD4 + T cells compared to unstimulated CD4 + T cells. We also found that IFT20 interacted with tumor susceptibility gene 101 (TSG101), a protein that endocytoses ubiquitinated T-cell receptors. The interaction between IFT20 and TSG101 promoted SMAC formation, which led to amplification of AKT-mTOR signaling. However, IFT20-deficient CD4 + T cells showed SMAC malformation, resulting in reduced CD4 + T cell proliferation, aerobic glycolysis, and cellular respiration. Finally, mice with T-cell-specific IFT20 deficiency exhibited reduced allergen-induced airway inflammation. Thus, our data suggest that the IFT20-TSG101 axis regulates AKT-mTOR signaling via SMAC formation.
Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients
Authors: Clémence M. Canivet, Ming-Hua Zheng, Sami Qadri, Luisa Vonghia, Kee-Huat Chuah, Charlotte Costentin, Jacob George, Angelo Armandi, Leon A. Adams, Naomi F. Lange, Odile Blanchet, Valérie Moal, Ramy Younes, Marine Roux, Wah-Kheong Chan, Nathalie Sturm, Mohammed Eslam, Elisabetta Bugianesi, Zhengyi Wang, Jean-François Dufour, Sven Francque, Hannele Yki-Järvinen, Kenneth I. Zheng, Jérôme Boursier
Journal: Clinical Gastroenterology and Hepatology (2023)
Differences in incidence, nature of symptoms, and duration of long COVID among hospitalised migrant and non-migrant patients in the Netherlands: a retrospective cohort study
Authors: Felix Patience Chilunga, Brent Appelman, Michele van Vugt, Kirsten Kalverda, Patrick Smeele, Josien van Es, Willem Joost Wiersinga, Mikael Rostila, Maria Prins, Karien Stronks, Marie Norredam, Charles Agyemang
Journal: The Lancet Regional Health - Europe (2023)

Comprehensive data on long COVID across ethnic and migrant groups are lacking. We investigated incidence, nature of symptoms, clinical predictors, and duration of long COVID among COVID-19 hospitalised patients in the Netherlands by migration background (Dutch, Turkish, Moroccan, and Surinamese origin, Others).We used COVID-19 admissions and follow up data (January 2021-July 2022) from Amsterdam University Medical Centers. We calculated long COVID incidence proportions per NICE guidelines by migration background and assessed for clinical predictors via robust Poisson regressions. We then examined associations between migration background and long COVID using robust Poisson regressions and adjusted for derived clinical predictors, and other biologically relevant factors. We also assessed long COVID symptom persistence at one-year post-discharge.1886 patients were included. 483 patients had long COVID (26%, 95% CI 24-28%) at 12 weeks post-discharge. Symptoms like dizziness, joint pain, insomnia, and headache varied by migration background. Clinical predictors of long COVID were female sex, hospital admission duration, intensive care unit admission, and receiving oxygen, or corticosteroid therapy. Long COVID risk was higher among patients with migration background than Dutch origin patients after adjustments for derived clinical predictors, age, smoking, vaccination status, comorbidities and remdesivir treatment. Only 14% of long COVID symptoms persisted at one-year post-discharge.There are significant differences in occurrence, nature of symptoms, and duration of long COVID by migration background. Studies assessing the spectrum of functional limitation and access to post-COVID healthcare are needed to help plan for appropriate and accessible healthcare interventions.The Amsterdam UMC COVID-19 biobank is supported by the Amsterdam UMC Corona Research Fund and the Talud Foundation (Stichting Talud). The current analyses were supported by the Novo Nordisk Foundation [NNF21OC0067528].
Deep learning based automatic detection algorithm for acute intracranial haemorrhage: a pivotal randomized clinical trial
Authors: Tae Jin Yun, Jin Wook Choi, Miran Han, Woo Sang Jung, Seung Hong Choi, Roh-Eul Yoo, In Pyeong Hwang
Journal: npj Digital Medicine (2023)

Acute intracranial haemorrhage (AIH) is a potentially life-threatening emergency that requires prompt and accurate assessment and management. This study aims to develop and validate an artificial intelligence (AI) algorithm for diagnosing AIH using brain-computed tomography (CT) images. A retrospective, multi-reader, pivotal, crossover, randomised study was performed to validate the performance of an AI algorithm was trained using 104,666 slices from 3010 patients. Brain CT images (12,663 slices from 296 patients) were evaluated by nine reviewers belonging to one of the three subgroups (non-radiologist physicians, n = 3; board-certified radiologists, n = 3; and neuroradiologists, n = 3) with and without the aid of our AI algorithm. Sensitivity, specificity, and accuracy were compared between AI-unassisted and AI-assisted interpretations using the chi-square test. Brain CT interpretation with AI assistance results in significantly higher diagnostic accuracy than that without AI assistance (0.9703 vs. 0.9471, p < 0.0001, patient-wise). Among the three subgroups of reviewers, non-radiologist physicians demonstrate the greatest improvement in diagnostic accuracy for brain CT interpretation with AI assistance compared to that without AI assistance. For board-certified radiologists, the diagnostic accuracy for brain CT interpretation is significantly higher with AI assistance than without AI assistance. For neuroradiologists, although brain CT interpretation with AI assistance results in a trend for higher diagnostic accuracy compared to that without AI assistance, the difference does not reach statistical significance. For the detection of AIH, brain CT interpretation with AI assistance results in better diagnostic performance than that without AI assistance, with the most significant improvement observed for non-radiologist physicians.
Neurological damages in COVID‐19 patients: Mechanisms and preventive interventions
Authors: Sibani Sarkar, Subhajit Karmakar, Malini Basu, Pratyasha Ghosh, Mrinal K Ghosh
Journal: MedComm (2023)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a novel coronavirus, causes coronavirus disease 2019 (COVID‐19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi‐organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia‐driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS‐CoV‐2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID‐19 associated damage to the central nervous system, patients need special care to prevent multi‐organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant‐based prevention therapies for COVID‐19‐associated neurological damage that leads to multi‐organ failure.
CAR-NK cell therapy for hematological malignancies: recent updates from ASH 2022
Authors: Ruihao Huang, Qin Wen, Xi Zhang
Journal: Journal of Hematology & Oncology (2023)

Abstract Chimeric antigen receptor (CAR)-NK cell therapy has the advantages of a low incidence of side effects and a low cost. However, the clinical outcomes are not satisfactory due to limited antitumor effects and a limited proliferative capacity. Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and multiple myeloma. This correspondence summarizes the preclinical and clinical updates for universal CAR-NK cell therapy reported at the ASH 2022 annual meeting.
USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities
Authors: Naiara Perurena, Rebecca Lock, Rachel A. Davis, Srivatsan Raghavan, Natalie F. Pilla, Raymond Ng, Patrick Loi, Caroline J. Guild, Abigail L. Miller, Ewa Sicinska, James M. Cleary, Douglas A. Rubinson, Brian M. Wolpin, Nathanael S. Gray, Sandro Santagata, William C. Hahn, Jennifer P. Morton, Owen J. Sansom, Andrew J. Aguirre, Karen Cichowski
Journal: Cell Reports Medicine (2023)

Pancreatic ductal adenocarcinomas (PDACs) frequently harbor KRAS mutations. Although MEK inhibitors represent a plausible therapeutic option, most PDACs are innately resistant to these agents. Here, we identify a critical adaptive response that mediates resistance. Specifically, we show that MEK inhibitors upregulate the anti-apoptotic protein Mcl-1 by triggering an association with its deubiquitinase, USP9X, resulting in acute Mcl-1 stabilization and protection from apoptosis. Notably, these findings contrast the canonical positive regulation of Mcl-1 by RAS/ERK. We further show that Mcl-1 inhibitors and cyclin-dependent kinase (CDK) inhibitors, which suppress Mcl-1 transcription, prevent this protective response and induce tumor regression when combined with MEK inhibitors. Finally, we identify USP9X as an additional potential therapeutic target. Together, these studies (1) demonstrate that USP9X regulates a critical mechanism of resistance in PDAC, (2) reveal an unexpected mechanism of Mcl-1 regulation in response to RAS pathway suppression, and (3) provide multiple distinct promising therapeutic strategies for this deadly malignancy.
CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness
Authors: Simona Mutascio, Talia Mota, Lavinia Franchitti, Ashish A. Sharma, Abigail Willemse, Sydney N. Bergstresser, Hong Wang, Maura Statzu, Gregory K. Tharp, Jared Weiler, Rafick-Pierre Sékaly, Steven E. Bosinger, Mirko Paiardini, Guido Silvestri, R. Brad Jones, Deanna A. Kulpa
Journal: Immunity (2023)

HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8